Veprek Pavel, Hajdúch Marian, Dzubak Petr, Kuklík Rostislav, Polakova Jana, Bezouska Karel
Group of Glycoconjugates, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 16610 Prague 6, Czech Republic.
J Med Chem. 2006 Oct 19;49(21):6400-7. doi: 10.1021/jm050741g.
Comblike glycodendrimers were prepared by the chemoselective ligation of cysteine-modified glycopeptides (1-7) with a 3-maleimidopropionate-modified linear synthetic carrier (8). Glycodendrimers bearing mono-, di-, or tri-Tn clusters (9-11) were tested as inhibitors using plant and mammalian lectins. In the former group, the Codium fragile lectin showed moderate discrimination among 9, 10, and 11. In the latter group, A and B isoforms of rat NKR-P1 lectin strongly discriminated between 9 and 10. 10 caused a 4-fold increase in killing of the NK resistant tumor cell lines at concentrations as low as 10(-8) M. Surprisingly, 11 interacted exclusively with the rat NKR-P1B isoform and inhibited efficiently natural killing in both rats and humans, even in the presence of the activating compounds 9 and 10. Dinitrophenol haptenization or influenza virus hemagglutinin T-cell epitope conjugation increased the immunogenicity of the parent compounds and resulted in the production of Tn specific antibodies.
梳状糖树状大分子是通过将半胱氨酸修饰的糖肽（1-7）与3-马来酰亚胺丙酸修饰的线性合成载体（8）进行化学选择性连接制备而成。携带单、二或三聚Tn簇的糖树状大分子（9-11）作为抑制剂，使用植物和哺乳动物凝集素进行了测试。在前一组中，脆弱刚毛藻凝集素在9、10和11之间表现出适度的区分能力。在后一组中，大鼠NKR-P1凝集素的A和B亚型在9和10之间有强烈的区分。10在低至10(-8) M的浓度下，能使NK抗性肿瘤细胞系的杀伤率提高4倍。令人惊讶的是，11仅与大鼠NKR-P1B亚型相互作用，并有效抑制大鼠和人类的自然杀伤作用，即使在存在激活化合物9和10的情况下也是如此。二硝基苯酚半抗原化或流感病毒血凝素T细胞表位偶联增加了母体化合物的免疫原性，并导致产生Tn特异性抗体。
